The efficient and regioselective synthesis of the naphthoquinone core of streptovaricin U

Article abstract of DOI:10.1039/a704596d

The efficient and regioselective synthesis of the naphthoquinone core of streptovaricin U 1 via the Diels-Alder reaction of 1-methoxy-2-methyl-3-trimethylsilyloxybuta-1,3-diene 5 with the 2,6-dibromo-3-methyl-1,4-benzoquinone 6 is described.

Full text of DOI:10.1039/a704596d

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The efficient and regioselective synthesis of the naphthoquinone core of
streptovaricin U
Masaaki Miyashita,*a Takahiro Yamasaki,b Tomonori Shiratani,b Susumi Hatakeyama,b Masahiro Miyazawaa
and Hiroshi Irieb
a Division of Chemistry, Graduate School of Science, Hokkaido University, Hokkaido 060, Japan
b Faculty of Pharmaceutical Sciences, Nagasaki University, Nagasaki 852, Japan
The efficient and regioselective synthesis of the naphthoqui-
none core of streptovaricin U 1 via the Diels–Alder reaction
of 1-methoxy-2-methyl-3-trimethylsilyloxybuta-1,3-diene 5
with the 2,6-dibromo-3-methyl-1,4-benzoquinone 6 is de-
scribed.
convenience. Thus butan-2-one 2 was treated with NaH and
HCO2Me in THF at 0 °C to give the sodium enolate 3, which
was treated, after the solvent was replaced from THF to DMF,
with dimethyl sulfate to give trans-4-methoxy-3-methylbut-
3-en-2-one 47 in 79% yield.† The butenone 4 was quantitatively
transformed into the silyloxy diene 5 by treatment with LDA in
THF followed by addition of Me3SiCl. The crude diene 5 thus
obtained was used directly for the Diels–Alder reaction. On the
other hand, 2,6-dibromo-3-methyl-1,4-benzoquinone 6, the
dienophile for the Diels–Alder reaction, was synthesized
according to the protocol of Trost and Pearson8 in two steps; (i)
bromination of m-cresol with Br2 in AcOH; (ii) oxidation of the
resulting tribromide with chromium(iii) oxide in AcOH (90%
yield for the two steps).
The streptovaricin family are representative ansamycin anti-
biotics as well as rifamycins and have been used clinically as an
important class of antibiotics.1 So far more than fifteen
congeners have been isolated from Streptomyces spectabilis and
all consist of a unique naphthoquinone core and a poly-
propionate ansa chain composed of nine contiguous chiral
centres.1 The unique structures and important biological activity
of the streptovaricins have elicited considerable attention from
synthetic chemists.2
The key Diels–Alder reaction was performed by heating a
mixture of the diene 5 (4.1 mmol) and the dibromoquinone 6
(3.2 mmol) in benzene (20 ml) at 90 °C for 2 h in a sealed tube
(Scheme 2). After cooling, the solvent was evaporated under
Recently we reported the highly stereoselective synthesis of
the ansa chain segment of streptovaricin U 1 and protostrepto-
O
OH OH OH OH
H
N
CO2H
O
OMe
O
O
Br
HO
Br
Br
i, ii
O
+
Streptovaricin U 1
HO
Me3SiO
O
O
6
varicins including nine contiguous chiral centres3 by the use of
the stereospecific methylation of g,d-epoxy acrylates with
trimethylaluminium.4 Streptovaricin U 1 is a unique open-chain
ansamycin from the streptovaricin family and shows inhibitory
activity against RAUSCHER leukemia virus RNA-dependent
DNA polymerase.5 We now report the highly efficient synthesis
of the naphthoquinone core of streptovaricin U 1 via the Diels–
Alder reaction of the silyloxy diene 5 with the dibromoquinone
6.
5
7
iii 85% from 6
O
O
O
N
PPh3
Br
iv
MeOCH2O
MeOCH2O
MeOCH2O
MeOCH2O
O
9
8
Although
1-methoxy-2-methyl-3-trimethylsilyloxybuta-
v
68% from 8
1,3-diene 5 is a known compound and has often been used in
Diels–Alder reactions,6 we prepared it by the modified
procedure shown in Scheme 1 for improved yield and synthetic
O
O
NH2
NHBoc
vi
85%
ONa
MeOCH2O
O
O
i
10
11
+ 3 HCO2Me
vii 83%
O
O
2
3
OMe
OMe
ii 79%
NH2
NHBoc
viii
OMe
OMe
87%
iii
MeOCH2O
OMe
OMe
13
12
Me3SiO
O
Scheme 2 Reagents and conditions: i, C6H6, sealed tube, 90 °C, 2 h; ii, 2%
HCl, DME, 12 h; iii, MeOCH2Cl, Pri2NEt, CH2Cl2, 3.5 h; iv, NaN3, PPh3,
DMSO, 3 h; v, aq. HCHO, THF, 2 d; vi, H2, PtO2, Boc2O (5 equiv.), EtOH,
3 h, then O2, 12 h; vii, H2, PtO2, EtOH, 1 h, then (MeO)2SO2 (10 equiv.),
1 m NaOH, 2 h; viii, Ph2O, 185 °C, sealed tube, 12 h
5
4
Scheme 1 Reagents and conditions: i, NaH (1.5 equiv.), THF, 0 °C, 1 h; ii,
(MeO)2SO2 (2 equiv.), DMF, 0 °C, 1 h, then 1 m aq. K2CO3, MeOH; iii,
LDA, THF, 278 °C, then Me3SiCl, 278 °C to room temp.
Chem. Commun., 1997
1787

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reduced pressure and the residue was treated with 2% HCl in
DME, giving rise to the adduct 7. The crude product 7 was
subsequently treated with ClCH2OMe and Pri2NEt in CH2Cl2 to
afford the protected bromoquinone 8 as light yellow crystals
(mp 169–172 °C) in 85% overall yield. Subsequent conversion
of 8 to the aminonaphthoquinone 10 was accomplished by the
reaction of 8 with NaN3 and PPh3 in DMSO followed by
treatment of the resulting iminophosphorane 9 with aqueous
formaldehyde in THF. Thus the desired aminonaphthoquinone
10 was obtained as red crystals (mp 177–179 °C) in 68% yield.
Although compound 10 is itself the naphthoquinone core of
streptovaricin U 1, it is necessary to further transform it into the
naphthalene derivative 13 for the coupling reaction with the
ansa chain segment, since the amino group on a naphthoquinone
ring such as 10 is not sufficiently basic for further transforma-
tion. The conversion of 10 into the target molecule 13 was,
however, unexpectedly troublesome and required ingenuity.
Eventually the desired transformation was overcome by the
following reaction sequence. Hydrogenation of 10 over Adams’
catalyst in EtOH in the presence of di-tert-butyl dicarbonate
(Boc2O) followed by treatment with oxygen gave rise to the
N-Boc-aminonaphthoquinone 11 as light yellow crystals (mp
141–143 °C) in 85% yield. The product 11 was subsequently
converted to the naphthalene dimethyl ether 12 (mp
104–106 °C) by hydrogenation over Adams’ catalyst in EtOH
followed by treatment of the resulting dihydroquinone with
dimethyl sulfate and 1 m NaOH in 83% yield. The synthesis of
the fully functionalized aromatic core 13 of streptovaricin U 1
was accomplished by removal of the Boc group in 12 by
thermolysis in Ph2O at 185 °C (sealed tube), resulting in
formation of 13 in 87% yield.
This work was also supported by a Grant-in-Aid for
Scientific Research on Priority Areas (No. 08245101) and a
Grant-in-Aid for Scientific Research (No. 09874149) from the
Ministry of Education, Science, Sports, and Culture of Japan.
Footnotes and References
* E-mail: miyasita@schem.ec.hokudai.ac.jp
† All new compounds exhibited satisfactory spectra (1H and 13C NMR, IR)
and elemental analyses.
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Thus an efficient and regioselective synthesis of the naph-
thoquinone core of streptovaricin U 1 has been established. The
overall yield of 13 from the dibromoquinone 6 was 35%. The
manipulations employed in the conversion of 10 into 13 may be
widely applicable to the synthesis of various aminonaphthoqui-
nones. The coupling reaction of the aromatic core 13 with the
ansa chain segment toward the total synthesis of 1 is now in
progress.
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Received in Cambridge, UK, 1st July 1997; 7/04596D
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Chem. Commun., 1997